There have been many approaches to meet the problems of regulating the delivery of proteins or peptides to biological systems or environments in the proper place, at the proper time, and at the proper dose to achieve a desired effect. These systems generally depend on the utilization of physical or chemical stimuli in the surrounding environment. Further, these environmental stimuli are usually of an external nature to the drug delivery system. Mechanisms that respond to such stimuli or signals include protein binding, hydrogel expanding or swelling, polymer erosion, membrane reorganization, solubility change, energy conversion, supply of activation energy for permeation, physical property changes of the materials that comprise the system, or phase transition phenomena, and the like. Examples are presented in J. Heller, Chemically self-regulated drug delivery systems, J. Control. Rel., 8, 111-125 (1988).
Recently, there has been an increasing interest in developing new protein delivery systems which are both safe and deliver the proteins or peptides in a more controlled manner. Additionally, it has become increasingly desirable to prolong protein delivery over several weeks or even more. Commonly employed pharmaceutical delivery devices include the use of implants, microcapsules, microspheres, and/or nanospheres in the form of nondegradable carriers, biodegradable carriers, or absorbable carriers. Additionally, other microparticle methods of controlled drug release have included the use of micelles, liposomes, etc.
Nondegradeable carriers include silicone rubber, polyethylene, polymethyl methacrylate(PMMA), polystyrene(PST), ethylene-vinyl acetate copolymer(EVA), polyethylene-maleic anhydride copolymers, polyamides, and others. Though, these carriers may be effective and sometimes useful, the implanted or injected compounds remain in the body as a foreign material after release of the protein and may require a surgical procedure for their removal. Additionally, nondegradeable carriers may also cause certain side effects in the body.
Conversely, when using biodegradable and/or absorbable carriers, the carrier is gradually degraded or absorbed in the body simultaneously with or subsequent to the protein release. In fact, biodegradable polymers can be designed to degrade in vivo in a controlled manner over a predetermined time period. Suitable biodegradable polymers for use in such sustained release formulations are well described elsewhere and include polyesters such as poly(D,L-lactide), poly(D,L-lactide-co-glycolide), poly(ε-caprolactone), poly(hydroxybutylic acid), and poly amino acids, poly(ortho ester)s, polyanhydrides, and poly(alkyl cyanoacrylate)s. These polymers gradually become degraded by enzymatic or non-enzymatic hydrolysis when placed in an aqueous physiological environment. The main mechanism of in vivo degradation for many polymers is hydrolytic degradation in which enzymes may also play a role. Important factors influencing hydrolytic degradation include water permeability, chemical structure, molecular weight, morphology, glass transition temperature, additives, and other environmental factors such as pH, ionic strength, and site of implantation, to name a few.
Whether microparticles, implants, environment responsive gels, or the like are in the form of nondegradable carriers, biodegradable carriers, or absorbable carriers, a unifying principle among all of these drug delivery mediums is a more prolonged and controlled protein delivery process.
Various microencapsulation techniques incorporating a protein or peptide into a microparticle carrier are taught in the prior art. However, microparticles having a biodegradable polymer matrix are especially valuable for reasons suggested above. Methods of making biodegradable microparticles include: (a) phase separation by emulsification and subsequent organic solvent evaporation (including complex emulsion methods such as O/W emulsions, W/O emulsions and W/O/W emulsions), (b) coacervation-phase separation, (c) melt dispersion, (d) interfacial deposition, (e) in situ polymerization, (f) spray drying and spray congealing, (g) air suspension coating, and (h) pan coating, to name a few.
Turning now to biocompatible polymers (including block copolymers, copolymers and the like) capable of existing in a gel state, such polymers are also useful for more prolonged and controlled protein or peptide delivery. In fact, polymers that are sensitive to their environment are especially useful. Environmental conditions that may effect these type of polymers include changes in temperature, pH, ionic strength, solvent, pressure, stress, light intensity, electric field, magnetic field, and/or specific chemical triggers such as glucose. Polymeric gels containing a desired protein or peptide may be administered in a liquid or gel state by a variety of pathways including via parenteral, ocular, topical, transdermal, vaginal, urethral, buccal, transmucosal, pulmonary, transurethral, rectal, intrarespiratory, nasal, oral, aural, sublingual, conjunctival, or by other known methods of administration. Once protein or peptide laden biocompatible and/or biodegradable polymers are administered, the polymer will release the protein or peptide into the body as it biodegrades, is absorbed, or is otherwise reduced to non-toxic products.
Though the aforementioned methods, i.e., microparticles, implants, and environment responsive gel delivery, have been somewhat effective in controlling protein or peptide delivery in the body, there have also been some limitations with these individual technologies. For example, a known problem with many drug delivery systems involve the effect commonly referred to as burst. Burst occurs as the drug delivery system releases more of a bioactive agent, such as a protein, than is desirable at a given time. The result of burst is that the desired uniform delivery of the protein to the body is undermined. In other words, in some cases, biodegradable polymers under in vivo conditions can have an initial level of medicament release (or at some other time) which is too high or too low.
Other limitations include the fact that many biologically active macromolecules, such as proteins and peptides, have low stability. This is particularly true when placed under the harsh fabrication conditions as are present when preparing protein or peptide delivery compositions, e.g., exposure to organic solvents, air-liquid interface, vigorous agitation, sonication, etc. Additionally, many proteins and peptides are highly water soluble.
In the prior art, attempts have been made to stabilize and/or reduce the solubility of proteins and peptides by complexing the proteins or peptides with multivalent cations such as zinc, calcium, magnesium, copper, ferric iron, and nickel, to name a few. For example, zinc complexed insulin is sparingly water-soluble and may be formulated into long-acting depots. Additionally, as disclosed in U.S. Pat. Nos. 5,912,015 and 5,891,478, human growth hormone (hGH) has been complexed with zinc ion to produce a precipitate. This precipitate has been incorporated into microspheres for a one-month sustained delivery in a biological environment. However, neither of these patents disclose the deposit of proteins or peptides onto biocompatible sparingly soluble particles in order to stabilize and/or prolong the release of proteins from a drug delivery biopolymer. Thus, it would be desirable to provide such a composition so that the solubility of the protein and/or the dissolution rate of protein from a drug delivery biopolymer device are reduced.